PROJECT SUMMARY The complaint of fatigue is common among patients receiving radiation therapy (RT) for the treatment of cancer, yet the mechanism of this fatigue is unknown. Many patients report drowsiness with RT, suggesting that sleepiness is contributing to their complaint of fatigue. But drowsiness, like fatigue, is a subjective complaint, which may not correlate with objective measurements of sleepiness and activity. Identifying objectives correlates of fatigue, including sleepiness and reduced activity, will be critical to advancing our understanding of underlying mechanisms. Understanding these mechanisms can lead to new therapies. The studies proposed in this Exploratory/Developmental Research Grant (R21) project will fill a gap in our understanding of the biological mechanisms of fatigue associated with radiation therapy for cancer. The hypothesis motivating this proposal is that sleepiness, reduced activity, and impaired vigilance associated with EGF cytokine elevation contributes to the fatigue experienced by patients receiving radiation therapy for prostate cancer. To test this hypothesis, we plan to measure before, and during RT the following: (1) Levels of the cytokine HB-EGF, (2) activity, (3) subjective sleepiness, (4) objective sleepiness, and (5) fatigue. We will make the same measurements also in a cohort of subjects with prostate cancer who are not treated with RT. All measurements except for objective sleepiness will be repeated at least three months after RT is completed. In each of these five measurements, we hypothesize a change on RT from baseline values. We will test our over-arching hypothesis that the pathway leading to the complaint of fatigue on RT treatment involves an elevation of HB-EGF, reduced activity, and increased sleepiness.